Multiple myeloma was responsible for the deaths of more than 12,000 Americans in 2006 and remains incurable with current therapy. MV-NIS is a recombinant measles virus that targets myeloma plasma cells and codes for the human thyroidal sodium iodide symporter, NIS. MV-NIS infected cells express the NIS protein on their surface membrane and therefore concentrate radioiodine. During the first five years of this grant we used noninvasive imaging techniques to study the spread of MV-NIS in myeloma xenograft models, and used I-131 to achieve synergistic tumor cell killing (radiovirotherapy). We also introduced the NIS gene into an oncolytic vesicular stomatitis virus (VSV) platform and used VSV-NIS for radiovirotherapy in the orthotopic syngeneic 5TGM1 myeloma model. MV-NIS is now being tested in a phase I clinical trial in patients with multiple myeloma and we plan to proceed (sometime in the next five years) to a follow-on clinical trial in which a therapeutic dose of I-131 will be administered after MV-NIS. Our goal during the next five years of this grant is to develop clinically viable approaches that will enhance the therapeutic index of radiovirotherapy. With this goal in mind, we have the following specific aims: Aim 1. To determine the rates of radioiodine efflux from myeloma deposits infected with viruses that code for NIS, plus or minus a shRNA that suppresses CLC(N)2 chloride channel expression. The hypothesis is that radioiodine escapes from most mammalian cells via the chloride channel, CLC(N)2 and can be retained more efficiently in myeloma cells by constraining the expression of this channel. Aim 2. To determine whether dexamethasone can ameliorate the bone marrow toxicity of I-131. The hypothesis is that dexamethasone, administered with radiovirotherapy will significantly decrease the bone marrow toxicity of the treatment without retarding the propagation of the virus or the expression of NIS in myeloma cells, and will thereby lead to improved treatment outcome. Aim 3. To determine whether the proteasome inhibitor bortezomib, an approved antimyeloma drug that sensitizes myeloma cells to the lethal effects of ionizing radiation, can enhance the oncolytic potency of radiovirotherapy using MV-NIS or VSV-NIS. The hypothesis is that bortezomib, administered with radiovirotherapy will significantly enhance the radiosensitivity of the tumor without retarding the propagation of the virus or the expression of NIS in myeloma cells, and will thereby lead to improved treatment outcome. Despite the introduction of new treatments, multiple myeloma remains incurable. The studies to be pursued in this grant combine the promising novel approach of oncolytic virotherapy with the use of radioactive iodine for the treatment of this disease.